There are rapid and significant advances being made in neuroscience and genetics. Where these two areas blend together we have the relatively new field of neurogenetics. In a recent compilation of human neurogenetic disorders, there were over 900 entries. For most of these diseases, little is known about the causes. The goal of this research is to gain a better understanding of the genetic controls in the developing mammalian central nervous system and to apply genetic techniques to the study of normal and abnormal development. The experiments include studies of normal and neurological mutant mice. A very basic question that can be asked about any human or mouse neurological disorder is: In which cell type(s) is the mutant gene acting? This question can seldom be answered because the most obviously affected cell type is not necessarily the actual site of gene action since there are multitudes of cell interactions occurring in the developing and mature nervous system. However, by producing chimeric mice, which contain mixtures of genetically normal and mutant cells, it is possible to compare the genotype of the cell with its phenotype and in that way determine whether the gene in question acts intrinsic to the cell or extrinsic to it. The mutant mice to be studied are animal models for such human diseases as neuronal degenerations, cerebellar ataxias, retinitis pigmentosa and spina bifida. Another area in which chimeric mice will be utilized is in studies of the role of cell lineage in the development of the nervous system. Although the mature nervous system appears highly organized, some developmental studies suggest a considerable amount of cell mingling occurs. The studies proposed are aimed at determining when the mingling occurs and how it relates to the mature nervous system. Finally, anti-nuclear antibodies will be produced for three purposes: 1) as strain-specific cell genotype markers for use in the above studies, 2) as cell type-specific markers as a reflection of biochemical differentiation between different cell types, and 3) as stage-specific markers reflecting temporal gene expression in different cell types.